AIDSWEEKLY Plus, Monday, 19 May 1997
Daniel J. DeNoon, Senior Editor
A new vaccine strategy would force HIV to expose crucial epitopes normally hidden from the immune system.
The strategy, still on the drawing board, is based on new insights into HIV gained from the identification of cellular chemokine receptors as necessary for HIV infectivity.
Harvard researcher Craig Gerard described these studies - and their implications for vaccine strategies - in a plenary presentation to the 9th Annual Meeting of the National Cooperative Vaccine Development Groups for AIDS (NCVDG), held May 4-7, 1997, in Bethesda, Maryland.
Gerard suggested that HIV fuses to cells only after a two- step process. In step one, interactions with the cellular CD4 molecule trigger a conformational change in the viral envelope. This change leads to step two, in which previously hidden viral epitopes bind to the co-receptor molecule and spring the HIV gp41 harpoon-like mechanism that penetrates the cell membrane.
"It may be possible to mimic this two-step process with antibodies," Gerard proposed. "A first set of antibodies would impact the conformational change of the fusion epitope normally achieved by CD4. A second set of antibodies might mimic binding of CCR5 [the co-receptor molecule] to spring gp41."
The Harvard researcher noted that two different cellular chemokine receptors are implicated in HIV binding: CXCR4 (also known as fusin, LESTR, and HUMSTSR), expressed on nearly all cells; and CCR5, expressed only on monocytes and some T cells.
The ability of the chemokine receptors to mediate HIV binding is independent of their normal function of signalling to white blood cells when and where they are needed. Gerard reported that HIV could still bind to chemokine receptors with mutations that abolished signal transduction.
Macrophage-tropic (M-tropic) HIV strains require CCR5, while T-cell-tropic (T-tropic) HIV strains use CXCR4.
Gerard found that M-tropic HIV strains require the two- step binding process: they must bind CD4 to expose their gp41 binding epitope; binding of this epitope to CCR5 triggers gp41 fusion.
But T-tropic HIV strains use a different strategy: they do not require CD4 binding to expose the epitope that binds to CXCR4.
This difference may explain why M-tropic HIV strains are much more likely to cause infection than T-tropic strains, and why T-tropic strains reemerge later in HIV disease.
"For M-tropic strains, critical epitopes are hidden from the immune system," Gerard said. "The immune system may select against CXCR4-using viruses early in infection. Later, when the immune system falters, CXCR4-using viruses will rapidly grow out."
This hypothesis also would explain why HIV is so pernicious.
"Since the crucial epitopes that spring this trap are hidden, it is very hard to stop this process," Gerard said.
He thus suggested that antibodies could be designed to prematurely spring the fusion trap, exposing HIV to elimination by the immune system. Such antibodies ideally would be elicited by vaccines, but might also be administered passively.
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